title: Dyskerin depletion increases VEGF mRNA internal ribosome entry site-mediated translation.
abstract: Dyskerin is a nucleolar protein encoded by the DKC1 gene that (i) stabilizes the RNA component of the telomerase complex, and (ii) drives the site-specific pseudouridilation of rRNA. It is known that the partial lack of dyskerin function causes a defect in the translation of a subgroup of mRNAs containing internal ribosome entry site (IRES) elements such as those encoding for the tumor suppressors p27 and p53. In this study, we aimed to analyze what is the effect of the lack of dyskerin on the IRES-mediated translation of mRNAs encoding for vascular endothelial growth factor (VEGF). We transiently reduced dyskerin expression and measured the levels of the IRES-mediated translation of the mRNA encoding for VEGF in vitro in transformed and primary cells. We demonstrated a significant increase in the VEGF IRES-mediated translation after dyskerin knock-down. This translational modulation induces an increase in VEGF production in the absence of a significant upregulation in VEGF mRNA levels. The analysis of a list of viral and cellular IRESs indicated that dyskerin depletion can differentially affect IRES-mediated translation. These results indicate for the first time that dyskerin inhibition can upregulate the IRES translation initiation of specific mRNAs.
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum-Universita' di Bologna, Bologna 40126, Italy, Centro Interdipartimentale di Ricerche sul Cancro 'Giorgio Prodi'-CIRC, Alma Mater Studiorum-Universita' di Bologna 40138, Italy and Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Rocchi
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pacilli
authors.forename: Rajni
authors.initials: R
authors.lastname: Sethi
authors.forename: Marianna
authors.initials: M
authors.lastname: Penzo
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schneider
authors.forename: Davide
authors.initials: D
authors.lastname: Treré
authors.forename: Maurizio
authors.initials: M
authors.lastname: Brigotti
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Montanaro
mesh_terms: D020121:5' Untranslated Regions; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D006801:Humans; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D010442:Peptide Chain Initiation, Translational; D034622:RNA Interference; D012333:RNA, Messenger / Q000737:chemistry; D012367:RNA, Viral / Q000737:chemistry; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D020121:5' Untranslated Regions; D018797:Cell Cycle Proteins; C112148:DKC1 protein, human; D009687:Nuclear Proteins; D012333:RNA, Messenger; D012367:RNA, Viral; D042461:Vascular Endothelial Growth Factor A